Opiate withdrawal, or abstinence, syndrome is the constellation of dilated pupils, coryza (runny nose), irritability, nausea and/or vomiting and/or diarrhea, and piloerection (goose flesh) in the setting of decrease or absence of opioid dosing or during the introduction of an opioid antagonist (e.g. naloxone or naltrexone). This syndrome is often associated with opioid addiction, because many addicts cannot maintain their supply of opioids and do not de-escalate their dosing prior to running out of drug. However the presence of an abstinence syndrome is not the most essential component of addiction, as addiction is “a behavioral pattern characterized by compulsive use of a drug and overwhelming involvement with its procurement and use” despite known harmful effects (Goodman & Gillman's The Pharmacological Basis of Therapeutics, J. G. Hardman (Ed.), McGraw-Hill Professional Publishing, 2001, p. 586). One part of potential treatment of addiction is the management of opioid abstinence syndrome. Opioid addicts can be very tolerant to opioids and therefore suffer severe and/or prolonged abstinence syndrome when they attempt to stop their self destructive behavior. Many medications have been utilized to decrease or prevent opioid abstinence syndrome beginning with methadone in the 1970s. In addition some medications have been studied to decrease the opioid “hunger” of addicts. These medications are considered treatment for opioid addiction.
At present, there are many medications being tested to treat opioid addiction, for example: Abbott 69024, Amantidine, Bupropion, Bromocriptine, Buspirone, Carbamazepine (Tegretol), Fluoxetine (Prozac), Flupenthixol, Gepirone, LAAM, Mazindol, Naltrexone and Schering 23390 (see ref: Scientific American, March 1991, pp. 94-103). Very few of these drugs have proven effective. New drugs are aimed at replacing methadone for opioid dependence, such as buprenorphine, however, only limited clinical study information is available (Fudula et al., NIDA Research Monograph 1991, 105:587-588).
Continuous opioid abuse during pregnancy has particular importance, as this can lead to complications in the mother and her baby. It is a recommended practice to maintain opioid-dependence in pregnant women with synthetic opioids. According to international guidelines, methadone is the recommended substance. However, a neonatal abstinence syndrome (NAS) is observed in 60-80% of neonates having a longer duration, but less severity, in comparison to NAS after heroin consumption during pregnancy (Eder et al., Psychiatr Prax 2001, 28:267-69). NAS may be characterized by one or more of the following: tremor, irritability, hypertonicity, vomiting, sneezing, fever, poor suckling, and convulsions.
Recent studies have investigated the safety and efficacy of other synthetic opioids, including sublingual buprenorphine, for the treatment of pregnant patients. Maintenance therapy with buprenorphine has proven safety and efficacy during pregnancy, where the mother was free of continuous heroin abuse, as verified through supervised urine-toxicology (Eder et al., Psychiatr Prax 2001, 28:267-69).
Buprenorphine is a potent, partial agonist of the μ-opioid receptor that has been shown to be effective to control pain in a wide range of patients when delivered by a number of different routes of administration, including intravenously, epidurally, intrathecally, or sublingually in both young and elderly patients (Inagaki et al., Anesth Analg 1996, 83:530-536; Brema et al., Int J Clin Pharmacol Res 1996, 16:109-116; Capogna et al., Anaesthesia 1988, 43:128-130; Adrianensen et al., Acta Anaesthesiol Belg 1985, 36:33-40; Tauzin-Fin et al., Eur J Anaesthesiol 1998, 15:147-152; Nasar et al., Curr Med Res Opin 1986, 10:251-255). There are several types of transdermal formulations of buprenorphine reported in the literature. See, for example, U.S. Pat. No. 5,240,711 to Hille et al., U.S. Pat. No. 5,225,199 to Hidaka et al., U.S. Pat. No. 5,069,909 to Sharma et al., U.S. Pat. No. 4,806,341 to Chien et al.; U.S. Pat. No. 5,026,556 to Drust et al.; U.S. Pat. No. 5,613,958 to Kochinke et al.; and U.S. Pat. No. 5,968,547 to Reder et al. Transdermal delivery systems of buprenorphine, made by Lohmann Therapie-Systeme GmbH & Co., are currently sold in the European Union under the trademark name TRANSTEC®. These patches contain 20, 30, and 40 mg of buprenorphine, with an approximate delivery or “flux” rate of 35, 52.5, and 70 μg/hr, respectively. Transdermal delivery systems of fentanyl, another opioid antagonist, are commercially available, e.g., under the name Duralgesic.
Buprenorphine has been shown in humans to be a potent opioid antagonist analgesic not displaying the psychotomimetic effects sometimes found with other antagonist analgesics. In animal and human tests, buprenorphine has been shown to have both agonist (morphine-like) and (morphine) antagonist properties. However from direct dependence studies in animals and in humans it has been concluded that buprenorphine does not produce significant physical dependence and the potential to produce psychological dependence is low as indicated by animal self administration studies and by the measurement of euphorigenic effects in human post addicts. In humans the agonist and narcotic antagonist characteristics of buprenorphine have been demonstrated in opiate addicts. Thus oral buprenorphine in the dose range 6-16 mg has been shown to precipitate abstinence in highly dependent opiate addicts presenting for detoxification. On the other hand in a study involving subjects stabilized on a relatively low daily dose of oral methadone, sublingual buprenorphine could be substituted for methadone with only a low level of discomfort. In this situation buprenorphine was behaving as an opiate agonist of low intrinsic activity.
A recent study has assessed the outcome of drug dependent mothers and influence of buprenorphine maintenance on neonatal morbidity (Jernite et al., Arch. Pediatr., 1999, 6(11):1179-85). This study showed that the use of buprenorphine during pregnancy may reduce dependence complications in the fetus/infant such as prematurity, growth retardation, fetal distress and fetal death.
The consequences of active opioid abuse to the fetus in the pregnant addict include: decreased oxygenation resulting in damage to multiple organs due to respiratory depression in the mother; malnutrition in utero due to maternal malnutrition from opiate induced inanition or confusion; abnormal neural development due to opiate exposure during development resulting in down regulation of opiate receptors and alternate abnormal neural pathway development; exposure to other fetal toxins, since most illegally obtained opiates are contaminated; exposure to other fetal toxins due to impaired judgment of the opiate intoxicated mother; and exposure to trauma (intentional and accidental) due to impaired judgment of the opiate intoxicated mother.
Information on the direct and indirect effects of buprenorphine on the fetus is essential for determining its potential for treatment of the pregnant opiate addict. In addition, therapeutic levels of buprenorphine in maternal circulation may have no indirect effects (via the placenta) on the fetus (Nanovskaya et al., J. Pharmacology and Exp. Ther. 2002, 300:26-33). This study observed that low transplacental transfer of buprenorphine to the fetal circuit may explain the moderate/absence of neonatal withdrawal in the limited number of reports on mothers treated with the drug during pregnancy. Furthermore, buprenorphine treatment appears to be well accepted by pregnant mothers, compared to methadone treatment, as demonstrated by compliance with therapy (Fischer et al., Addiction 2000, 95(2):239-244). Current buprenorphine treatment for addiction prevents and treats abstinence syndrome and may decrease opioid “hunger.” Buprenorphine for opioid addiction is delivered via daily or alternate day sublingual tablets or sublingual solution.
While methadone is the only opioid against currently approved in the US for maintenance therapy, buprenorphine has many of the desired characteristics of a treatment for opiate dependence: (a) the ability to substitute for opiates in moderately dependent individuals; (b) very mild abstinence effects when the drug is withdrawn; and (c) very good safety.
For maintenance treatment, however, there are potential problems of a sublingual buprenorphine product for the treatment of opiate addicts, such as the requirement for frequent dosing. This limits the mobility of the addict during treatment and often produces a perception that returning to a productive life will be difficult due to scheduling supervised dosing.
Thus, the lack of effective therapies for the treatment of drug dependence for both the general population and specifically drug dependent pregnant woman strongly suggests that novel approaches are needed. The present invention is directed to meeting this and other needs, and provides a method directed to the prevention and/or treatment of abstinence syndrome in opioid dependent pregnant women and their fetuses.